A dual role for PGLYRP1 in host defense and immune regulation during <i>B. pertussis</i> infection.

Abstract

<i>Bordetella pertussis</i>, the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed. Host recognition of bacterial peptidoglycan (PGN), including <i>B. pertussis</i> extracellular PGN fragment tracheal cytotoxin (TCT) shapes the immune response to infection. Peptidoglycan recognition proteins (PGLYRPs) are a conserved innate immune family that bind bacterial PGN and are primarily known for bactericidal activity in mammals; however, their immune modulatory roles are beginning to gain appreciation. The role of PGLYRPs in mammalian host defenses to Gram-negative pathogens, such as <i>B. pertussis</i>, remains largely unknown. Here, using knockout mice, single-cell and bulk transcriptomics, and functional assays, we identify a dual role for PGLYRP1 in modulating host immune responses to <i>B. pertussis</i>. PGLYRP1 contributes to antibacterial responses and paradoxically dampens inflammatory responses and inhibits bacterial killing later in infection. Mechanistically, PGLYRP1 enhances NOD1 signaling in response to TCT while suppressing NOD2- and triggering receptor expressed on myeloid cells-1 (TREM-1)-mediated inflammatory pathways. TCT-bound PGLYRP1 selectively impairs TREM-1 activation compared to PGNs from other bacteria. These findings demonstrate that <i>B. pertussis</i> co-opts PGLYRP1 to alter immune signaling, revealing a novel immune evasion mechanism with implications for vaccine design and host-directed therapeutics.